doi:10.1093/brain/awh716 Brain (2005) Page 1 of 13

Cortical spreading depression and peri-infarctdepolarization in acutely injured humancerebral cortex

Martin Fabricius,1 Susanne Fuhr,1 Robin Bhatia,2 Martyn Boutelle,3 Parastoo Hashemi,3

Anthony J Strong2 and Martin Lauritzen1

1Department of Clinical Neurophysiology, Glostrup Hospital, University of Copenhagen, Denmark, 2Department of ClinicalNeurosciences, King’s College London and 3Department of Bioengineering, Imperial College London, University ofLondon, London, UK

Correspondence to: Martin Fabricius, Department of Clinical Neurophysiology, Glostrup Hospital, DK-2600, DenmarkE-mail: Fabricius@dadlnet.dk

Electrocorticographic (ECoG) activity was recorded for up to 129 h from 12 acutely brain-injured humanpatients using six platinum electrodes placed near foci of damaged cortical tissue. The method probesECoG activity in the immediate vicinity of the injured cortex and in adjacent supposedly healthy tissue. Sixout of twelve patients displayed a total of 73 spontaneous episodes of spreading depression of the ECoG. Of theremaining 6 patients 1 displayed an episode of synchronous depression of ECoG during surgery. Using the sameelectrodes we also measured the slow potential changes (SPC) (0.005–0.05 Hz) to test the hypothesis that theECoG depressions were identical to Leao’s cortical spreading depression (CSD), and to be able to record peri-infarct depolarisations (PIDs) in electrically ‘silent’ cortical tissue. Changes in the SPC indicate depolarizationof brain tissue. For the analysis, the SPCs were enhanced by calculating the time integral of the ECoG signal.Spreading ECoG depressions were accompanied at every single recording site by stereotyped SPCs, whichspread across the cortical mantle at 3.3 (0.41–10) mm/min (median, range), i.e. at the same speed of spread asthe depression of the ECoG activity. The amplitude of the SPCs was 0.06–3 mV. In 4 out of 6 patients the ECoGrecovered spontaneously. In 2 patients we subsequently recorded recurrent SPCs, but without recovery of theinitial ECoG background activity until 2–5 h later. This represents the first direct recording of PIDs in acutelyinjured human brain. Evidence from this and our previous study of 14 brain-injured patients suggests that CSDsin acute brain disorders occur at higher incidence in patients <30 years (83%) than above (33%). CSD wasrecorded in 4 out of 5 traumatic brain injury patients, and in 2 out of 7 patients with spontaneous haemorrhages.We conclude that the spreading ECoG depressions recorded in patients are identical to CSDs recorded inanimal experiments. We furthermore provide direct electrophysiological evidence for the existence of PIDsand hence a penumbra in the human brain. We hypothesize that the depolarization events might contribute totissue damage in acute disorders in the human brain.

Keywords: brain injury; electroencephalography; electrocorticographic; penumbra; spreading depression

Abbreviations: AC = alternating current; CSD = cortical spreading depression; DC = direct current; ECoG =

electrocorticographic; GCS = Glascow coma scale score; ICU = intensive care unit; NMDA = N-methyl-D-aspartate;PID = peri-infarct depolarisation; SPC = slow potential change

Received April 29, 2005. Revised August 29, 2005. Accepted November 10, 2005

IntroductionWe investigated the occurrence in patients with two types of

severe, but transient depolarization of the cerebral cortex.

These phenomena are well characterized in animal experi-

ments, but their occurrence in the human brain is disputed.

First, cortical spreading depression (CSD) is a wave of per-

vasive failure of brain ion homeostasis that transiently inter-

rupts cortical function in the intact brain (Leao, 1944b;

Martins-Ferreira et al., 2000). It has been considered until

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recently an experimental phenomenon that requires to be

specifically ‘induced’. Secondly, peri-infarct depolarizations

(PIDs) are ‘spontaneous’ waves that propagate through the

penumbra region of cortical infarcts or traumatized cortex

into normally perfused tissue where they take on the charac-

teristic features of CSD (Nedergaard and Hansen 1993;

Nilsson et al., 1993; Strong et al., 1996). CSD in the intact,

normally perfused brain does not lead to cell death

(Nedergaard and Hansen 1988), while recurrent PIDs in the

injured brain are associated with increases in final infarct

volume (Gill et al., 1992; Mies et al., 1993; Back et al.,

1996; Busch et al., 1996; Takano et al., 1996). Moreover,

the infarct increases stepwise for each PID (Busch et al.,

1996). The incidence of CSDs and PIDs in experimental anim-

als can be strongly attenuated by appropriate blockers of

glutamate receptors (Marrannes et al., 1988; Park et al.,

1988; Lauritzen and Hansen, 1992; Hossmann, 1994;

Ohta et al., 2001). Accordingly, treatment with N-methyl-

D-aspartate (NMDA)-receptor antagonists significantly

reduced the final infarct volume in experimental focal isch-

aemia (Mies et al., 1993). This implied a possible new treat-

ment to limit brain injury, but clinical studies using these

neuroprotective agents have so far been disappointing

(Heiss et al., 1999; Lees et al., 2000; Sacco et al., 2001). One

explanation for this failure may be that only a subset of

patients with acute brain disorders develops CSDs or PIDs,

and that only this group will benefit from treatment such as

NMDA-receptor antagonists. If so, it is important to docu-

ment to what extent these phenomena occur in acute brain

injury, and to identify patient groups that are prone to

develop CSDs or PIDs.

We recently described repeated waves of transient

depression of electrocorticographic (ECoG) activity in

brain-injured patients. The waves spread across the cortical

mantle with the same speed as CSD in animal experiments

(Strong et al., 2002). The data suggested that CSD or CSD-like

events occurred in a large proportion of patients with acute,

focal brain damage. The recordings supposedly represented

events of severe cortical depolarization, but the frequency

range that was used did not allow detection of slow waves

of tissue depolarization. In animals, an �20 mV negative

direct current slow potential change (SPC) lasting �1 min

is the hallmark of CSD and PID (Leao, 1951; Koroleva and

Bures, 1996). This phenomenon invariably accompanies the

ECoG suppression and reflects the dramatic changes of the

intra- and extracellular ion concentrations which are an integ-

ral part of the massive depolarization of neurons and glia

characteristic of CSD (Kraig and Nicholson, 1978; Hansen

and Zeuthen, 1981; Somjen, 2001). The demonstration of

SPCs in the human brain would furnish proof that the depres-

sions of cortical activity we have observed are indeed CSD.

Furthermore, recording of SPC in electrically silent tissue

would enable us to demonstrate the occurrence of PIDs.

In animals, an intracortical glass microelectrode connected

to a direct current (DC) amplifier against a remote reference

is a straightforward way to record the SPC. However,

long-term intracranial DC recordings easily become unstable

in humans, unless measures are taken against this. We here

describe a methodology that allowed us to record SPCs from

human cerebral cortex for up to 129 h. Our data provide

direct and definite evidence for the existence of PIDs in the

acutely injured human brain and demonstrate that the ECoG

depressions observed previously are identical to Leao’s CSD

(Leao, 1944b).

MethodsPatient recruitment and clinical careThe research monitoring protocol was approved by the local research

ethics committee (London). After a clinical decision had been

made that surgery was required, clinical and research consents

were obtained. In 12 consecutive patients with traumatic (n = 5)

or spontaneous (n = 7) intracranial haematomas and/or subarach-

noid haemorrhage requiring craniotomy, we placed an ECoG record-

ing strip on the cortex accessible from the craniotomy. The lead cable

from the strip was tunnelled under the skin and exteriorized through

a stab wound to allow removal of the strip at end of monitoring

without re-opening the wound. In three of the patients, a microdia-

lysis probe was inserted next to the ECoG strip. The results of micro-

dialysis in these and in nine other patients have been published

separately (Parkin et al., 2005). After surgery, patients were trans-

ferred to the intensive care unit (ICU), where core variables were

monitored continuously (arterial and intracranial pressures and

arterial oxygen saturation (SaO2, pulse oximetry). The intracranial

pressure transducer (Codman) was located on the same side as the

craniotomy and usually in the cortical parenchyma near the ECoG

strips (haematoma cases). These variables were logged continuously

into the same data set as the ECoG data.

All patients were ventilated, at least initially, but were paralysed

only exceptionally, and sedation was maintained with propofol

(n = 10), or with fentanyl and midazolam (n = 5). In eight of

these patients sedation was withdrawn during monitoring. In

three of the most recent patients, insulin therapy was used by the

intensive care team, aiming to keep plasma glucose within a target

range of 3.5–5.5 mM.

Location of cortical recordingsIf possible, the electrode strip was placed radiating away from the

lesioned area so that the electrodes would be in contact with pre-

sumably viable cortex (Fig. 1). In some trauma patients, the lesions

were widespread, and supposedly viable tissue was chosen for strip

placement between injured areas. In most cases, part of the electrode

strip was positioned outside the area of cortex exposed by crani-

otomy so that placement of the entire strip on a single gyrus,

although usually attempted, could not be verified.

ElectrocorticographyFour active data channels were acquired from a 6-electrode (linear

array) subdural strip (Wyler; platinum, 5-mm diameter, 10-mm

interval between electrode centres; Ad-Tech Medical, Racine, WI)

that was connected to two 2-channel pre-amplifiers (Bioamps,

ADInstruments, New South Wales) in a sequential bipolar fashion,

with Electrode 1 (most remote from lesion) used as ground (Fig. 1).

Thus, the recordings were from a strip of cortex of �4 cm in length

and yielded four ECoG channels, named A, B, C and D. The ECoG

Page 2 of 13 Brain (2005) M. Fabricius et al.

was recorded continuously for periods of up to 129 h. The lower

frequency limit of the alternating current (AC) amplifiers was

0.02 Hz (29% attenuation), but frequencies as low as 0.002 Hz

were detectable (90% attenuation). Accordingly, a monophasic

change of the DC potential lasting for 1–2 min could be recorded

albeit with a distorted form, since the AC amplifier returned the

derivative of the DC signal.

Data collectionThe ECoG data were digitized (100–200 Hz per channel) with a

Powerlab 16SP analogue/digital converter (ADInstruments) and

recorded with Chart software (ADInstruments) and a laptop com-

puter (Powerbook, Apple). Arterial blood pressure and oxygen

saturation, intracranial blood pressure and optional microdialysis

data were digitized simultaneously in the same system and files.

Analysis was performed on a PC using Chart software.

Data analysis and integrationEach transient period of ECoG amplitude reduction or loss was first

examined according to the criteria reported previously (Strong

et al., 2002). Recovery of the locally generated ECoG activity was

gradual, and isolated bursts occurred in the depressed part of the

curve, before continuous activity resumed. The time for recovery of

local activity was arbitrarily defined to the time point when bursts

occurred continuously at intervals shorter than 20 s.

We noticed that the baseline level of the unfiltered ECoG signal

slowly deviated predominantly in a negative direction for 1–3 min

just at the onset of the ECoG depressions. To amplify this slow

baseline deviation, and to reverse the derivative transformation

caused by the AC-filtration, we calculated the time integral of the

ECoG signal followed by a subtraction of the general slope of the

integral (300 s time constant decay) (Figs 2 and 3). This summarized

and amplified even small deviations of the baseline if lasting for

�>10 s, while the AC changes in the conventional EEG range

(0.5–30 Hz) summated to �0 because of phase cancellation. The

procedure resulted in visualization of an SPC, which developed

over 1–3 min synchronous with the spreading ECoG depressions.

The SPCs had opposite phases in adjacent channels which made it

possible to assign each component of the SPC to a single electrode

(Fig. 2). Here it is important to note that a bipolar montage as used in

the present study is made up of sequential linkages of channels of

equispaced electrodes along the electrode strip. Each channel is con-

nected to one pair of active electrodes and displays the potential

difference between them. If a localized change of the SPC occurs

at or near the electrode common to both channels, the signal will

deflect in opposite direction (phase reversal). This demonstrates the

active locus of the SPC. The two components of the SPC, one from

each of the electrodes contributing to a channel, may be more or

less clearly separated depending of the recovery time of the SPC

(Figs 2 and 4). The signal component derived from one single elec-

trode has a steep mono- or biphasic component preceded and fol-

lowed by slight deviations from the baseline. In two patients, we

observed recurrent stereotyped SPCs spreading between channels

during a prolonged period of depressed ECoG (Fig. 5). These epis-

odes were classified as PIDs (Table 1).

Power-analysis and criteria forspreading eventsFor enhancement of the ECoG signal (AC) variations in the con-

ventional EEG-frequency bands, the signal was filtered (0.5–70 Hz)

and squared to obtain the power. This improved our ability to detect

periods of ECoG depression by simple visual detection (Fig. 2). For

example, a reduction of the raw signal of �30% was represented as a

50% reduction of the power signal. Since these moderate depres-

sions were usually accompanied by spreading stereotyped SPCs, the

criteria for spreading events were modified accordingly (Table 1).

ResultsData for the 12 patients are summarized in Table 2. Mean

age was 48 years for females (n = 4) and 41 years for males

(n = 8). All traumatic brain injury patients were males (n = 5).

Trauma mechanisms were assault (n = 3), fall (n = 1) or road

traffic accident (n = 1). Of the non-traumatic cases, two

patients had subarachnoid haemorrhage due to intracranial

aneurysms, two had intracerebral haematomas due to an

arterio-venous malformation and three had spontaneous

haemorrhages, possibly due to hypertension and atheroscler-

osis. Injuries were located in the frontal, parietal and/or tem-

poral lobes (n = 8, 4, and 4). Initial preoperative Glasgow

coma scale score (GCS) was in the range 6–15. Six-month

recovery ranged between fatal outcome and upper good

recovery.

ECoG background activityMonitoring was initiated either in the final phase of surgery or

soon afterwards. The ECoG pattern when monitoring started

Fig. 1 Schematic diagram of electrode strip placement on thecortex with respect to injury and gyri. Electrode 6 is positionedover viable cortex next to contused tissue (black area). The visiblepart of the strip is placed along a gyrus and slipped under the edgeof cut dura and bone (not shown). Thus, Electrodes 1–4 areusually not visible. Signals from Electrodes 2–6 are amplified in adifferential montage to derive data channels A to D. Thick arrowsindicate possible course of a CSD along a gyrus, curving aroundsulci and reaching the electrode strip at different angles. In thisexample, the time required for the accompanying SPC to get fromElectrodes 4 to 3 will be long, resulting in a low apparent velocitycompared with Electrodes 5–4. Thin arrows indicate how a CSDspreading from another part of the lesion may eventually reach theelectrode strip from the other end.

Spreading depression in human cortex Brain (2005) Page 3 of 13

often showed a burst-suppression pattern, but within hours,

a continuous, but irregular 1–3 Hz (delta) activity was estab-

lished in most patients. Repeated CSD episodes changed

the background ECoG activity from delta waves to a burst-

suppression pattern which ceased when the cerebral cortex no

longer produced CSD. Focal seizure activity was detected in

two patients (Nos 1 and 7). The relationship of repeated seizure

activity with CSD is described in a separate publication.

CSDs and PIDsSix patients had a total of 73 episodes of CSD. Every episode

of ECoG activity depression was accompanied by stereotyped

SPCs. The spreading episodes radiated from the exposed

injury site (43%) or had the opposite direction (57%).

Fig. 2 Recording of CSD in the injured human cortex over aperiod of 40 min (Patient no. 4). Upper four traces show the ECoGrecorded in a differential chain from five electrodes (full scale1 mV). A 50–80% reduction of the ECoG amplitude spreads fromChannel A to C, while a 25% reduction of amplitude is seen inChannel D. Middle four traces show the same curves uponintegration of the signal (full scale 4 mVs) to enhance the slowpotential changes. Each depression in the upper traces isaccompanied by a stereotyped baseline change reflecting an SPC.Electrode numbers are indicated to mark the onset ofdepolarization at that particular electrode as evidenced by phasereversal. Thus, the SPC occurring exclusively in Channel Acompares to a depolarizing event at Electrode 2 alone, while aphase reversal between Channels A and B corresponds to anevent at Electrode 3, etc. Lower four traces show the power of the0.5–70 Hz band of the ECoG signal [full scale 0.03 mV2 (ChannelsA and D) or 0.12 mV2 (Channels B and C)]. The traces areamplified a little out of range to visualize loss of amplitude. Thereduced activity of Channel D is better appreciated herethan in the raw ECoG signal of the upper traces.

Fig. 3 Low-pass filtering versus integral: 20-min recording fromPatient no. 4. (Upper and lower traces are details from Fig. 2,only Channel D is shown here). Upper trace, baseline changes ofthe raw ECoG signal (full range 1 mV) are hardly visible. Middletrace shows a 0.05 Hz low-pass filtering of the upper trace, fullrange 0.1 mV. Two SPCs are readily visible, but so are otherdeflections due to baseline noise. Lower trace shows thetime-integrated signal (full range 3 mVs). Compared to thelow-pass filtered trace, abrupt baseline noise is much lessconspicuous. The initial electronegative part of the two SPCs ismore pronounced due to the integrating process that reverses thedifferentiating effect of the AC-filtering during recording.

Page 4 of 13 Brain (2005) M. Fabricius et al.

In 3 out of the 6 patients we encountered both directions of

spread in various episodes. In two patients (Nos 9 and 12)

(Fig. 5), local ECoG activity failed to recover for several hours

after a few episodes of CSD. In this period a total of 25 SPCs

continued to spread between the channels. The shape, dura-

tion and amplitude of the SPCs were similar to the previous

recordings taken at a time when background ECoG activity

was still obtained. Therefore, these episodes represent spread-

ing depolarization in otherwise electrically silent tissue,

i.e. PIDs. The medication of the patients was unchanged

immediately before and during these periods. Mean age for

the CSD/PID group (n = 6) was 38.3 versus 48.3 years for the

other six patients (not significant, P = 0.27 by t-test). The

overall age distribution was bimodal: all three patients

<25 years had CSD, while the remaining 9 patients (age

39–69) had an incidence of 33%. The initial evaluation of

the data using our original criteria (Strong et al., 2002)

showed 49 episodes of CSD as opposed to a total of 98 epis-

odes of CSD/PID using the present analysis.

Duration and timing of eventsThe duration of the period of depressed ECoG activity showed

a bimodal distribution (Fig. 6). In three patients (Nos 4, 5,

and 7) the CSD episodes (n = 54) had a short recovery time

of 6 min (2.5–11) (median, range). This compares well to

the recovery time for experimental CSD in the normally per-

fused brain (Leao, 1944b; Hansen and Zeuthen, 1981;

Martins-Ferreira et al., 2000). In three patients (Nos 1, 9

and 12) the recovery time was 8–22 min for the first CSD

episode, but became prolonged later. In one of these patients

(No. 1) the recovery time gradually increased up to 86 min

with eventual good recovery. In 2 out of 3 patients (Nos 9 and

12) the first CSD episodes were followed by persistently

depressed ECoG activity for 3.7 and 8 h, respectively, while

recurrent PIDs were recorded. At the end of this period, a

burst-suppression pattern gradually reappeared.

The time delay between the onset of monitoring and the

first depolarizing episode was 0.2–4.2 h. Most ECoG depres-

sions occurred at regular intervals of �30 min. A few series of

CSDs/PIDs showed repetition intervals of 8–12 min.

SPCEvery episode of transient ECoG depression was

accompanied by a marked and stereotyped slow baseline

change, i.e. an SPC (Fig. 2). The profile of the SPC varied

between patients, but remained largely constant within the

same patient given that the CSD propagated in the same

direction (Fig. 4). The SPCs lasted for 2–3 min for the larger

monophasic component, and 3–5 min for the biphasic steep

components (Fig. 4). The amplitude from peak to peak was

0.06–3 mV for the raw signal (Fig. 5), and 1.3–68 mVs for the

integrated signal (Figs 2 and 4). The well-defined shape of the

SPCs allowed the latency between onsets at two neighbouring

electrodes to be measured more accurately than the onset of

ECoG depressions. The latency varied between 1 and 24 min

corresponding to propagating velocities of 3.3 (0.41–10)

mm/min (median, range)—comparing favourably with the

results reported previously (Strong et al., 2002). The wide

range of velocities may be explained by variations in the ori-

entation of the propagating wave front with respect to the

electrode strip (Strong et al., 2002).

When the first part of the SPC appeared, the ECoG

background activity of that channel usually showed a

minor reduction of amplitude. The marked depression of

ECoG background activity usually coincided with the onset

of the late component of the SPC which reflects depression at

both electrodes recorded by that channel. Several recordings

showed an SPC spreading from channels showing an ECoG

depression into a neighbouring channel where ECoG back-

ground activity persisted. Probably, the CSD wave stopped at

the first electrode, while a sulcus prevented the wave reaching

the second electrode recorded by the latter channel. Thus, the

SPCs enabled us to demonstrate the spreading nature of

the events when ECoG depressions were only significant in

one channel.

Non-spreading episodesIn 6 out of the 12 patients no CSD episodes were recorded.

One of these six patients (No. 6) showed a single non-

spreading episode without accompanying SPC. The episode

Fig. 4 Three sets of 22-min recordings of integrated ECoG signalfrom three consecutive episodes of CSD (Patient no. 4). Thefigure illustrates that the ECoG signals for the same patient werestereotyped as indicated in this figure by superimposing tracesfrom three different CSD episodes.

Spreading depression in human cortex Brain (2005) Page 5 of 13

occurred during operation, when the middle cerebral artery

was clipped temporarily to bring the blood flow in the middle

cerebral artery to a transient hold. The ECoG depression

lasted for 6 min followed by a burst-suppression activity.

In Patient no. 1, a similar episode was recorded at 15 min

after the recordings commenced in the ICU. The two episodes

were not accompanied by an SPC, and were therefore not

explained by depolarization of the tissue. Thus, one possible

mechanism for the non-spreading events is temporary hypo-

perfusion causing transient silencing of the ECoG activity.

This question may be addressed in future studies that include

local CBF measurement. In our previous paper (Strong et al.,

2002), non-spreading episodes were encountered more fre-

quently. This difference is difficult to define, but could relate

to improvement of recording conditions in this study.

Case reportsPatient no. 4This 48-year-old male suffered multiple traumas in a road

traffic accident. CT-scan showed a left parietal and temporal

intracerebral haematoma and intraventricular haemorrhage.

Upon evacuation of the haematomas at 7.5 h after injury, the

electrode strip was placed over the left middle frontal gyrus.

Re-operation was performed at 16.5 h after injury to remove

a newly formed, extradural haematoma. Thrombocytopenia

was noted and corrected during the re-operation. During the

period of monitoring, the ICP remained >25 mmHg, steadily

climbing, but re-intervention was deemed inappropriate.

The patient developed sepsis and died after 11 days.

ECoG was monitored from 12.5 to 88.5 h after the accident

(Fig. 2). Initially, a pattern of burst-suppression activity was

detected. At 15 h after the accident, three episodes of CSD

were detected at 24–28 min interval. No further events were

detected for the following 38 h while the background

ECoG changed into a stable delta-activity. From 54 to 80 h

after the injury, six CSD episodes were recorded, accompanied

by remarkably stereotyped SPCs (Fig. 4). This was followed by

the reappearance of a burst-suppression pattern.

Patient no. 5This 24-year-old male was previously healthy but woke up

confused and vomiting. CT-scan showed a left frontoparietal

Fig. 5 Three hour recording of ECoG from Channels A to D (Patient no. 9). The three sets of traces represent the same period (samesetting as in Fig. 2): upper four traces show the unfiltered signal (full scale 3 mV). Middle four traces show the integrated signal (full scale100 mVs). Lower four traces show the power of the 0.5–70 Hz band of the signal (full scale: 0.05 mV2). Baseline ECoG activity showedburst-suppression pattern: 2 s bursts and 10–30 s suppressions, amplitude 300–1000 mV. Initially, a CSD spreading from Channel A to Ddepressed this ECoG activity for 30–40 min. The CSD was accompanied by SPCs and spread from Channels B to D at a velocity of2–3 mm/min (thin arrows). After �1 h another CSD accompanied by SPCs spread from D to A (thick arrows). This time, the ECoGactivity did not recover. After 29 min, SPCs spread from channel D to A with exactly the same time sequence and shape as detected duringthe last CSD. The ECoG remained depressed indicating compromised metabolism. The event was therefore classified as a PID. Twostereotyped PIDs followed after intervals of 32 and 39 min. Just before the last of these PIDs slight recovery of ECoG in Channel Dwas noticed (lower right). During 5 h a total of 21 stereotyped PIDs were recorded. These PIDs were either similar to those in the figure orspread in the direction A to D in a second stereotyped pattern.

Page 6 of 13 Brain (2005) M. Fabricius et al.

intracerebral haematoma, 3· 5 cm2, with midline shift.

Angiography revealed an arterio–venous malformation aris-

ing from suprasylvian middle cerebral artery branches, drain-

ing via a single vein to the superior sagittal sinus. At admission

the GCS was 12, but dropped to 7 prior to craniotomy, evacu-

ation of the haematoma and resection of the arterio–venous

malformation. ECoG monitoring over the left middle frontal

gyrus was started at 18.6 h post ictus. From 21.7 to 34 h post-

ictus, 11 episodes of CSD were recorded spreading from

Channel A. During this period, the ECoG background activity

of Channel A turned into a burst-suppression pattern, while

continuousdelta-activitypersistedintheotherchannels.Chan-

nel A gradually recovered over the first 3 h following the last

CSD, and for the next 10 h ECoG was stable. At this time,

right-sided arm and leg weakness were noted for the first

time. Recovery was slow; at 6 months the patient was dys-

phasic and hemiparetic: power in the right arm was MRC 3/5,

and in the leg, 4/5.

Patient no. 9This 67-year-old male was admitted after a fall. Initial GCS

was 13, but dropped to 10 after a few hours. CT-scan revealed

an extensive right hemisphere acute subdural haematoma,

with midline shift and right frontal lobe contusion. GCS

dropped further to three, and the pupils became non-

reactive bilaterally, before surgical evacuation of the subdural

haematoma. ECoG monitoring over the partially contused

right middle frontal gyrus started at 17.5 h after injury.

After 40 min of monitoring, we recorded 2 consecutive epis-

odes of depression of ECoG activity, accompanied by stereo-

typed spreading SPCs (Fig. 5). Following the first episode,

ECoG background activity returned, but after the second

episode the ECoG activity remained depressed in all channels.

Over the next 5 h, 21 stereotyped episodes of spreading SPCs

were detected. ECoG remained depressed for a total of 8 h,

after which a burst-suppression pattern developed and then

gradually recovered. Arterial oxygen saturation remained

>90% and no extra sedative was administered to the patient

in this period to explain the lack of cortical activity. The pupils

remained fixed; on the second day high blood pressure

and low pulse were noted, and deterioration continued

until death 2 days later.

Patient no. 12This 48-year-old man had a history of non-migrainous head-

aches, and his mother suffered from migraine with aura. The

patient was assaulted. GCS at the scene was 11. At admission,

he had generalized tonic-clonic seizures which were con-

trolled by diazepam, phenytoin loading and maintenance.

The patient was maintained on insulin in the ICU. CT

revealed a left temporal lobe contusion and haematoma

(burst lobe), left petrous temporal fracture, right frontal con-

tusion and right orbital fracture. The left temporal contusion

was evacuated, and an ECoG strip was placed over the left

superior temporal gyrus, close to the contused tissue. Mon-

itoring started at 21.2 h after injury. Initial ECoG showed

no evidence of cortical activity, but after 1.7 h a burst-

suppression pattern emerged. After another 40 min, six

CSDs were observed at 17–38 min intervals. The recovery

time increased from 8 to 25 min, presenting a sparse burst-

suppression pattern (40–50 s suppressions). After the last

CSD, ECoG background activity remained depressed for

Table 1 Criteria for ECoG events

ECoG SPC Comment

Synchronous ECoGdepressions

Simultaneous loss ofpower—ECoGamplitude of �50%, in twoor more channels

No accompanying SPC Must be distinguished fromabrupt loss of amplitude dueto movement artefacts

Spreading episodes,general definitions

Depressions: Loss ofpower—ECoGamplitude of 50%, graduallydeveloping over 30–60 s

Bi- or tri-phasic change inpotential of 2–5 min’ durationand 0.1–4 mV amplitude

Depressions may develop intwo steps separated byseveral minutes

CSD, fast recovery Depressions lasting for2–10 min in at leastone channel

Accompanying stereotyped andspreading SPC in at least thesame and the neighbouring channels

Normal recovery time whencompared with CSDs in theintact rodent brain

CSD, prolonged recovery Depressions lasting formore than 10 min in thefastest recovering channel

Latency for spreading betweenchannels within 0.5–25 min The prolonged recovery suggests

early or partial energy failure

PID No locally generated ECoGin any of the channels thatdisplay a spreading SPC

Stereotyped and spreading SPCsin at least two channels.Latency for spreading betweenchannels within 0.5–25 min

The occurrence of repeated SPCsin otherwise electrically silent tissuepoints to severe but incompleteenergy failure

CSD = cortical spreading depression; PID = peri-infarct depolarisation; ECoG = electrocorticogram; SPC = slow potential changes of ECoG

Spreading depression in human cortex Brain (2005) Page 7 of 13

Tab

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Page 8 of 13 Brain (2005) M. Fabricius et al.

3.7 h. During the first 80 min of this period four PIDs were

observed at intervals of 5–10 min. After another 2.5 h, the

ECoG background activity gradually recovered. At 19 and 23

h after recovery another two CSD episodes were observed with

recovery times of 6–18 min. No further events were observed

for the following 35 h while the ECoG gradually changed into

an almost continuous 1.5–2 Hz activity of low amplitude

(150 mV). After 2 weeks GCS was 14 (dysphasic). The patient

had lower moderate disability at 6-month follow-up.

DiscussionGeneralThe data presented here provide definite evidence that the

spreading depression of ECoG background activity, which can

be detected in cortical tissue in �50% of patients with

acute brain injury, is identical to Leao’s cortical spreading

depression (Leao, 1944b). We observed that every spreading

ECoG depression was accompanied by a stereotyped SPC,

which represents the depolarization of neurons and glia

that is an integral part of CSD. The profile, duration and

amplitude of the SPCs were consistent with the characteristics

of the DC potential changes observed during CSD in animal

experiments (Leao, 1951). The SPCs and the depression of the

ECoG background activity occurred at the same time and

propagated together in the cortical tissue that was monitored

by the electrode strip. The speed of spread of the SPCs was

similar to that of Leao’s CSD. Taken together this provides

definite evidence that the transient, spreading ECoG depres-

sions we have observed in human neocortex adjacent to a

brain lesion are CSDs. SPCs were also observed in two patients

with long-term depression of ECoG. This represents the first

electrophysiological recordings in humans of PID, character-

istic of the ischaemic penumbra (Nedergaard and Hansen,

1993). Repeated depolarizations of brain tissue, spreading

through cortical regions adjacent to cortical lesions are com-

mon in acutely injured human cortex. Whether PID/CSD

contributes to the expansion of the focal brain damage fol-

lowing the initial insult will need to be addressed in a future

study.

Long-term monitoring andslow potential changesIn pursuit of a therapeutic strategy, the main technical prob-

lem is to secure stable and sensitive recordings that may be

interpreted online, to allow selection of patients who might

benefit from drug intervention. The present paper describes

two important means of enhancing changes compatible with

CSD/PID during monitoring. Changes of signal amplitude are

more readily detected, and repeated stereotyped patterns of

these changes better appreciated, when the EEG-filtered signal

is displayed as a compressed power trend. The time-integrated

curves show SPCs during CSD/PID that are remarkably ste-

reotyped, and often easy to recognize. The combined mon-

itoring of the raw ECoG signal, power and integrated curves in

a 90-min compressed screen frame is a very efficient way to

monitor these patients (Fig. 2). With the use of this analytical

framework, and provided there are stable recording condi-

tions in the ICU, it is unlikely that a CSD or PID event will be

overlooked if it spreads below the monitoring strip. The loca-

tion of the strip is important for the sensitivity, but the CSD

may reach the strip from two or more different sources

(Fig. 1). We observed that in half of the patients the depol-

arization waves propagated along the strip in either direction.

This might suggest that CSD propagates over large areas of the

same cerebral lobe. Spread of PIDs between gyri is common

after middle cerebral artery occlusion in cats (gyrencephalic

brain) (Strong et al., 2000). On the other hand, experience in

some experiments in animals with gyrencephalic brains sug-

gests that sulci may represent barriers to CSD (Bowyer et al.,

1999a, 1999b), while major cytoarchitectonic changes may

block CSD in rodents, lisencephalic squirrel monkey cortex

Fig. 6 The recovery time of ECoG activity varied between andwithin patients. The time to return of locally generated ECoGactivity for 20 different episodes of CSD in six patients is shown.Bars represent the period of suppressed ECoG activity in ChannelA for separate episodes of CSD in a top–down time sequence.Patient identities (Table 2) are indicated along the vertical axis. Forsimplicity, only the first CSD episode within each 12-h interval ofrecording was included except for Patient no. 12, where thesuppression time was markedly prolonged episode by episode.Recovery time varied between 2.5 and 86 min. In 2 CSD episodes(Patients no. 9 and 12) ECoG activity remained depressed forseveral hours, while recurrent PIDs were recorded. A recovery ofthe ECoG within10 min, as indicated by the dotted line, wasconsidered fast while a depression lasting for >10 min indicatedprolonged recovery. The difference in recovery time betweenCSD episodes in a single patient represents variation over time inthe capacity of the tissue to regenerate transmembrane iongradients, i.e. variation in the match between energy demand andavailability. The figure also illustrates variability between patients.

Spreading depression in human cortex Brain (2005) Page 9 of 13

and larger gyrencephalic brains (Leao, 1944b; Rebert, 1970;

Bures et al., 1974). In all six patients displaying CSD, the first

CSD was observed within 4.2 h of start of recording. In one

patient three CSD episodes were observed at 16–18 h after

injury followed by a CSD-free period, while at 54 h new CSD

episodes were observed. This biphasic pattern of CSD epis-

odes is similar to the time distribution of CSD/PID in experi-

mental animals under conditions of focal brain damage that

induces transient PID/CSDs within the first 2 h post-injury,

while a second CSD peak is observed at 12 h (Hartings et al.,

2003). The 36-h CSD-free interval in this patient suggests that

a long observation period is needed for studies of CSD in the

acutely injured human cerebral cortex.

Electrophysiological evidence ofCSD in human brainBures and co-workers obtained the first direct evidence for

a CSD in human grey matter in vivo (Sramka et al., 1977).

They showed that microinjections of potassium chloride into

the caudate nucleus or the hippocampus elicited spreading

depressions. A large negative shift of DC potential was

observed in the hippocampus spreading at a rate of

3.2 mm/min, consistent with the propagation rate of CSD

in rodents. They obtained similar recordings in the caudate

nucleus. Notably, there was no suppression of the spontan-

eous electrical activity in the caudate nucleus recorded locally

while the CSD propagated. This was due to technical limita-

tions of the method: the electrodes were not positioned

along the path of propagation and the recordings were not

bipolar, but monopolar (Sramka et al., 1977). Another issue is

the pick-up area of the electrodes. The ECoG depression is

confined to an �30-mm wide band, which is surrounded by

much larger volumes of tissue with preserved ECoG activity.

This may explain the preserved spontaneous activity due to

volume conduction of activity from remote generators. Nev-

ertheless, the DC potential changes were unequivocal and

were taken as definite evidence of the existence of spreading

depression in human brain. The recording conditions that we

used in the present, and in our previous study (Strong et al.,

2002), took Bures’ considerations into account.

A second line of evidence comes from in vitro studies of

excised temporal cortical tissue from humans undergoing a

brain operation for epilepsy, or other intracranial disorders.

In one such study, Avoli et al. (1991) described DC changes

characteristic for CSD by exposing brain tissue to artificial

CSF with a reduced concentration of Mg2+. The CSD episodes

alternated with periods of seizure activity, and both patho-

logical reactions were blocked by NMDA-receptor antagonists

(Avoli et al., 1991). Speckmann’s group has successfully eli-

cited seizure activity and CSD in human brain slices as well,

and has demonstrated important interaction between the two

events (Gorji, 2001; Gorji and Speckmann, 2004). Thus, the

in vitro evidence is strong and provides direct evidence that

human brain cortex can and does support CSD.

The third line of evidence comes from the work of

Mayevsky who observed repetitive episodes of CSDs in a

head injured patient in vivo (i.e. in only 1 out of the 14 studied)

starting at �30 h after start of the monitoring (Mayevsky et al.,

1996). The recordings showed characteristic transients of pot-

assium, cerebral blood flow, cerebral blood volume, oxidation

of the cortex and ECoG suppression consistent with CSD.

Measurements were performed at a single point, therefore

the putative spreading nature of the events could not be

demonstrated. The recording equipment was positioned

over the hemisphere contralateral to the lesion for practical

reasons (Mayevsky et al., 1996), which may explain the low

incidence of CSD/PID episodes reported.

In comparison, we positioned the electrode strip immedi-

ately adjacent to the lesion, radiating into apparently normal

brain tissue. Most likely, this may explain why we found

evidence of CSD/PID in 50% of our patients with acutely

injured human brain cortex. It is likely that some CSD/PID

episodes escaped detection by our electrodes, because the

depolarization waves failed to propagate to the recording

site. However, we reasoned that the close proximity between

lesion and electrodes would minimize this shortcoming of

the methodology, and facilitate the detection of at least

some of CSD/PID episodes in patients in whom the reaction

occurred. In rodents, CSD spreads in all directions from the

point of stimulation, and in pigs CSDs have been found to

propagate into and out of sulci as well, even though the

velocity of spread is slower in the sulcus than on the crest

of the gyrus (Bowyer et al., 1999b). We observed slow velo-

cities of spread between some electrodes (0.4 mm/min) cor-

responding to a latency of 25 min between two neighbouring

electrodes, while a ‘normal’ propagation velocity in rodents is

�2–3 mm/min. The slower velocity of spread may correspond

to a ‘true’ travel length of �5 cm which may indicate spread

into a sulcus and up again. Additional studies using more

electrodes than in the present study would be needed to

describe in more detail the propagation characteristics of

CSD in the human brain, which are likely to be more complex

than in rodents.

PIDs and the ischaemic penumbraThe observations in two patients of a few initial CSDs fol-

lowed by repeated episodes of PIDs show that depolarizing

episodes may be linked to the expansion of the penumbra and

thereby potentially of the core infarct zone. In both patients a

period of repeated SPCs, in otherwise electrically silenced

cortex, was followed by 2.4–3 h of complete ECoG silence

followed by slow recovery of the ECoG activity. The reason

for the prolonged silencing of the ECoG after the depolariza-

tions could be a reduced blood flow in the penumbra region of

the traumatized tissue (Astrup et al., 1977). The fact that the

tissue were able to produce repeated SPC episodes suggests

that perfusion and in turn the substrate supply for brain

energy metabolism were sufficient for the re-establishing of

the ionic gradients across the cell membranes. Eventually, the

Page 10 of 13 Brain (2005) M. Fabricius et al.

ECoG background activity resumed, which suggests that the

tissue was indeed viable. We postulate that this is the first

electrophysiological evidence of a penumbra in human brain

tissue, and that the spreading SPCs which we have recorded

represent the human correlate of the PIDs recorded in experi-

mental focal brain injury.

In animals, a CSD/PID leads to a massive leaking of ions

over the cell membranes along the ion gradients, and the

subsequent re-establishment of the concentration gradients

of, e.g. sodium, potassium and calcium, is a heavy metabolic

task for the cells. In normally perfused tissue, local blood flow

increases �100% for more than a minute during CSD (Leao

1944a; Fabricius et al., 1995). The local oxygen tension may

transiently decrease or increase depending on the blood flow

reaction (Lehmenkuhler et al., 1976; Back et al., 1994; Wolf

et al., 1996), while the tissue lactate concentration increases

more than 100% for several minutes in the normally perfused

brain due to activation of glycolytic pathways (Lauritzen

et al., 1990; Scheller et al., 1992).

The hemodynamic and metabolic changes associated with

PIDs are different. Importantly, transient ‘reduction’ in tissue

pO2 is characteristic of PID (Back et al., 1994), and reductions

in perfusion of varying duration propagate across the cerebral

cortex coupled with the depolarization (Strong et al., 2003).

A microdialysis study of changes in extracellular glucose and

lactate in the penumbra indicated transient reductions in

glucose coupled with increases in lactate; the transient events

appear to be superimposed on a gradual decline in dialysate

glucose, suggesting that the supply of glucose for energy con-

sumption is compromized under these conditions (Hopwood

et al., 2005). This may explain in part the capacity of PIDs to

increase infarct size (Gill et al., 1992; Mies et al., 1993; Back

et al., 1996; Busch et al., 1996; Takano et al., 1996)

Clinical perspective in relationto treatmentCSD is efficiently blocked by NMDA antagonists in animals

(Lauritzen and Hansen, 1992) and man (Avoli et al., 1991;

Gorji, 2001). However, several intervention studies applying

NMDA-antagonists in largely unselected human brain trauma

patients have been unsuccessful (Heiss et al., 1999; Lees et al.,

2000; Sacco et al., 2001). We suggest that identification of

those patients that display CSD/PID may provide a means of

selecting those patients who are likely to benefit from treat-

ment with NMDA-receptor antagonists. The CSD/PID-prone

patients reported here displayed multiple episodes (nine or

more) and intervention could in principle be added after the

first or second episode. Propofol is known to block gap junc-

tions in vitro and might therefore be supposed to inhibit CSD

events, which in part depend on preserved function of gap

junctions (Nedergaard et al., 1995). It is worthy of note that all

six patients displaying CSD/PIDs were treated with propofol.

The dosage of propofol, however, was in the lower range,

and could have been insufficient to block gap junctions.

Nevertheless, it points to an important requirement for

future intervention studies: any anti-CSD treatment must

be monitored for effect until a dose–response relationship

has been established.

The occurrence of CSD/PID showed a possible dependence

on age. When 12 of the patients from our previous publication

(Strong et al., 2002) were included (excluding 2 patients who

were monitored for <12 h), the age-dependent incidence of

patients with CSD/PID was virtually the same as in the

present material: 21–24 years: 83% (n = 6); 39–69 years:

33% (n = 18). Incidence of trauma as the primary injury

for the young group was 66 versus 56% for older patients.

Therefore, a different mechanism of injury is not an obvious

explanation for this trend. Among the 24 patients, all the 6

young patients were males. In the older group there were 9

males and 9 females, and incidence of CSD/PIDs in both of

these gender groups was 33%. It is quite possible that CSD

may be a more common finding in young patients, who have a

better prognosis after brain injury. The finding needs to be

confirmed in a larger series, but may point to a target group

for an intervention study.

ConclusionsWe present direct and unequivocal electrophysiological evid-

ence for the existence of CSD and PID in human cerebral

cortex. We used the unfiltered ECoG, simple expressions as

power and ECoG integration to obtain this result, which

doubled the sensitivity of the ECoG for these types of events,

and made detection of PIDs possible. The method is robust

and may become a standard monitoring device in the ICU in

the future. For acutely injured patients, non-invasive methods

of CSD detection, preferably applied over periods of days, are

needed. Whatever methods emerge are likely to be less specific

than the ECoG of the exposed cortex, and for this reason any

one method will best be supported by simultaneous use of an

additional method. Eventually, this will determine to what

extent the large body of knowledge about CSD and focal

ischaemia in animals will be applicable to acute pathology

in the human brain. The clinical impact of pharmacological

blockade of CSD/PID events may become the subject of a

future intervention study, but in the first place it is necessary

to establish the impact of these events on outcome.

Note: We have initiated an international research group:

COSBID (CoOperative Study of Brain Injury Depolarisa-

tions). The primary goal of this group is to register ECoG

in a cohort of brain injury patients, and compare the occur-

rence of spreading events (CSD/PID) with outcome. Further

information is available at www.cosbid.org.

AcknowledgementsWe thank the patients and their relatives for their assistance

with the study, and the medical and nursing staff of the

Intensive Care Unit of King’s College Hospital, London,

for their support and collaboration. We are grateful to The

Wellcome Trust, GlaxoSmithKline, HeadFirst and the Rose-

trees Charitable Trust for financial support.

Spreading depression in human cortex Brain (2005) Page 11 of 13

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